Aryl boronate functionalized polymers for treating obesity

ABSTRACT

Disclosed are polymers comprising one or more phenyl boronate ester, boronamide or boronate thioester groups. The phenyl boronate ester, boronamide and boronate thioester groups are represented by one of the following structural formulas:  
                 
Ar in Structural Formulas (I) and (II) is substituted or unsubstituted; and each Z is —O—, —NH— or —S— and is independently selected. Pharmaceutically acceptable salts of the polymer are also included. The aryl boronate ester, boronamide or boronate thioester can be cleaved to release the corresponding aryl boronic acid. Also disclosed are pharmaceutical compositions comprising the polymers of the present invention and a pharmaceutically acceptable carrier or diluent; and methods of treating a subject for obesity with the polymers of the present invention.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/302,221, filed Jun. 29, 2001, and U.S. Provisional ApplicationNo.60/359,473, filed Feb. 22, 2002, the entire teachings of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

Human obesity is a recognized health problem with approximatelyninety-seven million people considered clinically overweight in theUnited States. Various chemical approaches have been used for treatingobesity. In one such approach, a medicament which inhibits lipases isadministered to the obese patient. Lipases are key enzymes in thedigestive system which break down diglycerides and triglycerides intomonoglycerides and fatty acids. Diglycerides and triglycerides have ahigh caloric content but are not absorbed by the small intestine untilbroken down by the lipases. Therefore, inhibition of lipases within thedigestive system results in a reduction in the absorption of fat andconsequently a decrease in caloric uptake. XENICAL is an example of acommercially available lipase inhibitor that is used for treatingobesity.

Administration of lipase inhibitors results in stools with a high fat oroil content from the undigested diglycerides and triglycerides. Leakageof oil from the stool is an unpleasant side effect that often occurswhen stools have a high fat or oil content. This condition is referredto as “oily stool” or “leaky stool”. It has been reported in U.S.application Ser. No. 09/166,453 that fat-binding polymers, whenco-administered with lipase inhibitors, can bind with or “stabilize” theoil and thereby reduce or eliminate the leakage of oil from the stool.However, the need to administer two drugs can reduce patient compliancebecause it is burdensome and inconvenient. The development of new drugswhich both inhibit lipases and bind the lipids which cause “leakystools” would be an advance with respect to managing and treatingobesity in patients.

SUMMARY OF THE INVENTION

It has now been found that polymers with aryl boronate ester, boronamideand boronate thioester groups that can be hydrolyzed to liberate arylboronic acids inhibit lipases in vivo (see Example 14). It is expectedthat mammals which have been administered fat binding polymers withthese cleavable aryl boronate ester, boronamide and boronate thioestergroups will have reduced levels of the “leaky stool” side effectcompared with other lipase inhibiting compounds. Based on thisdiscovery, novel polymers, including fat-binding polymers, withcleavable aryl boronate ester, boronamide and/or boronate thioestergroups and the use of such polymers for treating obesity are disclosedherein.

One embodiment of the present invention is a polymer comprising one ormore aryl boronate ester, boronamide and/or boronate thioester groupsrepresented by Ar-B-(Z-)₂ or Ar-B-(ZH)(Z-), wherein each Z is —O—, —NH—or —S— and is independently selected. Preferably, each Z is —O—. Thearyl boronate ester, boronamide or boronate thioester can be cleaved orhydrolyzed to release the corresponding aryl boronic acid. The arylgroup represented by Ar is substituted or unsubstituted. Preferably, thearyl boronic ester groups are phenyl boronic esters representedStructural Formulas (I) or (II):

Phenyl Ring A in Structural Formulas (I) and (II) is substituted orunsubstituted.

Another embodiment of the present invention is a pharmaceuticalcomposition. The pharmaceutical composition comprises the polymerdescribed above and a pharmaceutically acceptable carrier or diluent.

Another embodiment of the present invention is a method for removing fatfrom the gastrointestinal tract (or inhibiting uptake of fat in thegastrointestinal tract) of a subject in need of such treatment (e.g.,treating a subject for obesity). The method comprises the step ofadministering an effective amount of the polymer described above to thesubject.

The polymers disclosed herein are believed to release aryl boronic acidsin the gastrointestinal tract. Aryl boronic acids are potent inhibitorsof lipase enzymes. The polymers of the present invention are thereforeeffective in removing fat from the gastrointestinal tract of subjectsfor whom reduced fat absorbtion can be clinically beneificial. Thus,these polymers are useful in the treatment of obesity. Because many ofthe disclosed polymers bind the lipids, the unpleasant leakage of oilfrom the stools that often accompanies the administration of lipaseinhibitors is reduced or eliminated compared with other lipaseinhibiting drugs. The disclosed polymer drugs and many of the liberatedboronic acid groups are largely unabsorbed by the intestines andtherefore also have the advantage of causing minimal systemic sideeffects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic showing the synthesis of4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid chloride (6).

FIG. 2 is a schematic showing the synthesis of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-2,5-difluorophenylboronic acid(11).

FIG. 3 is a schematic showing the synthesis of (neopentyl glycolato)4-(14′-trimethylammonium-3′-thia-1′-ketotridecyl)-2,5-difluorophenylboronateester chloride (14).

FIG. 4 is a schematic showing the synthesis ofpoly-N-(3-diethanolaminopropyl)acrylamide (17).

FIGS. 5A-5F are a compilation of the structures of boronic acids whichcan be incorporated into the boronate functionalized polymers of thepresent invention. R in FIG. 5D is a C12 straight chained alkyl group.

DETAILED DESCRIPTION OF THE INVENTION

The polymers of the present invention comprise one or more cleavablearyl boronate ester, boronamide or boronate thioester groups. Theinvention is described below with respect to aryl boronate esters, i.e.,wherein each Z is —O—. It is to be understood that these descriptionsapply to the corresponding boronamides and boronate thioesters, i.e.,wherein one or both Zs are —NH— or —S—.

These polymers bind lipids in the gastrointestinal tract and alsoinhibit the action of lipase enzymes. “Cleavable” means that thecorresponding aryl boronic acid group is released from the polymer whenthe aryl boronate ester is hydrolyzed. Thus, the polymers of the presentinvention are limited to polymers in which the boronate ester group is“between” Ar (or Phenyl Ring A) and the polymer backbone and that theonly covalent linkage between the Ar (or Phenyl Ring A) and theremainder of the polymer is through the boronate ester bond(s). AlthoughApplicants do not wish to be bound by any particular mechanism, it isbelieved that the boronate ester functional group is hydrolyzed in vivo,thereby liberating an aryl boronic acid, which then acts to inhibit thelipase.

Ar and Phenyl Ring A in Structural Formulas (I) or (II) are substitutedor unsubstituted. Ar and Phenyl Ring A are “substituted” when Arcomprises at least one substituent and Phenyl Ring A comprises at leastone substituent other than the boronate ester group. Suitablesubstituents are as described below for aryl groups. Preferably, Ar andPhenyl Ring A are substituted with at least one electron with drawinggroup.

An electron withdrawing group is a substituent which results in a phenylring that has less electron density when the group is present than whenit is absent. Electron withdrawing groups have a Hammet sigma valuegreater than one (see, for example, C. Hansch, A. Leo and D. Hoeckman,“Exploring QSAR Hydrophobic, Electronic and Steric Constants”, AmericanChemical Society (1995), pages 217-32) Examples of electron withdrawinggroups include halogens, —NO₂, —CN and —X—R. X is —CHD-, —CD₂-, —COO—,—CONH—, —CO— or —SO₂—; D is a halogen; and R is a substituted orunsubstituted straight chained hydrocarbyl group with an ether,thioether, phenylene, amine or ammonium linkage. Additional values for Xinclude —S(O)— and —S(O)₂O—. In one aspect, the hydrocarbyl grouprepresented by “R” is a straight chained hydrocarbyl group with an etheror thioether linkage and optionally substituted at the terminal positionwith an amine, halogen, —CF₃, thiol, ammonium, alcohol, —COOH, —SO₃H,—OSO₃H or phosphonium group. In another aspect, the hydrocarbyl grouprepresented by R is a straight chained hydrocarbyl group with anammonium linkage and optionally substituted at the terminal positionwith an amine, halogen, —CF₃, thiol, ammonium group, alcohol, —COOH,—SO₃H, —OSO₃H or phosphonium group. In yet another aspect, thehydrocarbyl group represented by R is a straight chained hydrocarbylgroup substituted at the terminal position with an amine, halogen, —CF₃,thiol, ammonium group, alcohol, —COOH, —SO₃H, —OSO₃H or phosphoniumgroup.

Alternatively, R is —CH₂—O[—(CH₂)_(p)O]_(m)—(CH₂)_(p)—Y or—C(O)CH₂—S[—(CH₂)_(p)O]_(m)—(CH₂)_(p)—Y, p is 2 or 3, m is an integerfrom 1-5 and Y is an ammonium group.

A “straight chained hydrocarbyl group” is a polyalkylene group, i.e.,—(CH₂)_(x)— where x is a positive integer (e.g., between 1 and about30), preferably between about 6 and about 30, more preferably betweenabout 6 and about 15. A “linkage group” refers to a functional groupwhich replaces a methylene in a straight chained hydrocarbyl. Examplesof suitable linkage groups include an alkene, alkyne, phenylene, ether(—O—), thioether (—S—), amine [—N⁺(R^(a))]— or ammonium[—N⁺(R^(a)R^(b))—]. R^(a) and R^(b) are independently —H, alkyl,substituted alkyl, phenyl, substituted phenyl, or, taken together withthe nitrogen atom to which they are bonded, a non-aromatic,nitrogen-containing heterocyclic group. Preferably, R^(a) and R^(b) arenot —H. More preferably, R^(a) and R^(b) are both alkyl groups and evenmore preferably, both methyl. R^(a) and R^(b) can be the same ordifferent, but are preferably the same.

The terms “terminal position” or “terminus” refer to the methylenecarbon of the straight chained hydrocarbyl group most distant from Ar,Phenyl Ring A or Phenyl Ring B, as described below. Substituents at theterminal position of a straight chained hydrocarbyl group are referredto herein as “terminal substituents”. As noted above, examples ofsuitable terminal substituents include amine (—NR^(c)R^(d)), halogen,—CF₃, thiol, ammonium (—N⁺R^(c)R^(d)R^(e)), alcohol (—OH), —COOH, —SO₃H,—OSO₃H or phosphonium group. R^(c), R^(d) and R^(e) in an ammonium groupare independently —H, alkyl, substituted alkyl, phenyl, substitutedphenyl, or, taken together with the nitrogen atom to which they arebonded, a nitrogen-containing, non-aromatic heterocyclic group.Preferably, R^(c), R^(d) and R^(e) are not —H. More preferably, R^(c),R^(d) and R^(e) are all alkyl groups (i.e., a trialkylammonium group)and even more preferably, all methyl (i.e., a trimethylammonium group).R^(c), R^(d) and R^(e) can be the same or different, but are preferablyall the same.

In one aspect, the hydrocarbyl group represented by R is substituted atthe terminal position with a group —Y, wherein —Y is selected such thatYH is a small molecule polyamine. For example, when YH is a smallmolecule polyamine, —Y can be represented by —[NH—(CH₂)_(q)]_(r)—NH₂). qis an integer from 2 to about 10 and r is an integer from 1 to about 5.Examples of small molecule polyamines include spermine, spermidine,1,2-diaminoethane, 1,3-diaminopropane or 1,4-diaminobutane. Optionally,one or more of the secondary amine can optionally be N-alkylated orN,N-dialkylated; the primary amine is optionally N-alkylated,N,N-dialkylated or N,N,N-trialkylated.

A “substituted hydrocarbyl group” has one or more substituents bonded atone or more positions other than at the terminus. Suitable substituentsare those which do not significantly lower the lipase inhibiting abilityor fat binding ability of the polymer, for example, do not lower eitheractivity by more than a factor of about two. Examples of suitablesubstituents include C1-C3 straight chained or branched alkyl, C1-C3straight chained or branched haloalkyl, —OH, halogen (—Br, —Cl, —I and—F), —O(C1-C3 straight chain or branched alkyl) or —O(C1-C3 straightchain or branched haloalkyl).

In a preferred embodiment, the polymer of the present inventioncomprises one more phenyl boronate ester group represented by StructuralFormula (III):

R is as described above.

Phenyl Ring B is substituted or unsubstituted. Phenyl Ring B is said tobe “substituted” when it has one or more substituents other than —CO—Rand the boronate ester. Suitable substituents for Phenyl Ring B are asdescribed below for aryl groups. Preferably, Phenyl Ring B issubstituted with one or more electron withdrawing groups. Fluorine is apreferred electron withdrawing group for Phenyl Ring B. Examples ofsuitable substitution patterns for Phenyl Ring B include 3-fluoro and2,5-difluoro, wherein position 1 is the carbon bonded to boron.

In a more preferred embodiment, the phenyl boronate ester groups in thepolymers of the present invention are represented by Structural Formula(IV):

In Structural Formula (IV), Y is an ammonium group (preferablytrialkylammonium) and more preferably trimethylammonium) and n is aninteger from 1 to about 30, preferably from about 3 to about 30 and morepreferably from about 6 to about 15.

An arylboronate ester group (or phenyl boronate ester group) comprisesan aryl boronate portion (or a phenyl boronate portion) and an “esterportion”. The aryl boronate portion (or phenyl boronate portion) can beconnected directly or “linked” directly to the polymer by one or twoboronate ester bonds, in which case the “ester portion” is the polymerbackbone. Examples of polymers of this type include polyvinyl alcohol ora polysaccharide with an aryl boronate group(s) (or phenyl boronategroup(s)) bonded directly to the polymer backbone through one or twoboronate ester bonds formed between the boronate group and alcoholgroups from the polymer backbone. Alternatively, the “ester portion” isa side chain which is pendent from the polymer backbone and serves tolink or connect the aryl boronate group (or phenyl boronate group) tothe polymer backbone. In this case, the “ester portion” typicallycomprises at least one and preferably at least two alcoholfunctionalities which are suitably positioned to form boronate esterbonds with an aryl boronic acid (or a phenyl boronic acid), e.g., analkyldiol. Structural Formulas (V), (VI) and (VII) each show an exampleof a phenyl boronate ester formed from an alkyl-1,2-diol, analkyl-1,3-diol or an alkyl-1,5-diol, respectively, and a phenyl boronicacid:

Specific examples of monomers with side chains comprising alkyl-1,2-diolgroups are shown below:

The monomers can be polymerized and the alkyl-1,2-diol groups of theresulting polymer esterified with an aryl boronic acid to form aboron-functionalized polymer of the present invention. Alternatively,the alkyl-1,2-diol groups of the monomers can be esterified with an arylboronic acid and the resulting boron-functionalized monomer polymerizedto form a boron-functionalized polymer of the present invention. Each ofthe alkyl-1,2-diol functionalized monomers depicted above can beesterified, for example, with any one of the boronic acids shown in FIG.5.

Specific examples of monomers with side chains comprising alkyl-1,3-diolgroups are shown below:

The above monomers can be polymerized and the alkyl-1,3-diol groups ofthe resulting polymer esterified with an aryl boronic acid to form aboron-functionalized polymer of the present invention. Alternatively,the alkyl-1,3-diol groups of the monomers can be esterified with an arylboronic acid and the resulting boron-functionalized monomer polymerizedto form a boron-functionalized polymer of the present invention. Each ofthe alkyl-1,3-diol containing monomers depicted above can be esterified,for example, with any one of the boronic acids shown in FIG. 5.

Also included in the present invention are polymers comprising phenylboronamide and/or boronate esters groups corresponding to the structuresrepresented by Structural Formulas (III)-(VII), i.e., wherein one orboth boronate oxygen atoms is replaced with —S— and/or —NH—.

Optionally, the polymer side chains comprises a group which increasesthe ability of the polymer to bind fat, e.g., an amine group or acationic group such as an ammonium group. Thus, the side chain typicallycomprises an aminoalkyldiol, i.e., a moiety with one amine and twoalcohol groups or the corresponding ammonium group; or a dialkanolaminesuch as diethanolamine or the corresponding ammonium group. The“corresponding ammonium group” refers to the alkylated or benzylatedform of, for example, an aminoalkyldiol or dialkanolamine. Examplesinclude a phenyl boronate esters shown below in Structural Formulas(VIII)-(XI), which are formed from an aminoalkyl-1,2-diol,ammoniumalkyl-1,2-diol, a diethanolamine and diethanolammonium group anda phenyl boronic acid:

R₁₀ is —H, a substituted or unsubstituted alkyl group or a substitutedor unsubstituted benzyl group, preferably —H. R^(e) and R^(f) areindependently —H, a substituted or unsubstituted alkyl group or asubstituted or unsubstituted benzyl group, preferably —H.

Specific examples of monomers and polymers with side chains comprisingdiethanol amine groups are shown below:

The monomers shown above can be polymerized and the diethanolaminegroups of the resulting polymer esterified with an aryl boronic acid toform a boron-functionalized polymer of the present invention.Alternatively, the diethanolamine groups of the monomers can beesterified with an aryl boronic acid and the resultingboron-functionalized monomer polymerized to form a boron-functionalizedpolymer of the present invention. Each of the diethanolamine-containingmonomers depicted above can be esterified, for example, with any one ofthe boronic acids shown in FIG. 5.

In yet another aspect, side chains of the polymer are polyols with fouror more alcohol groups which can form boronate esters. Typically, aboronate ester is formed from two diols in the side chain and theboronic acid. The side chain can comprise more than one aryl boronateester. Examples of suitable monomers with polyol side chains are shownbelow:

The monomers shown above can be polymerized and the polyols of theresulting polymer esterified with an aryl boronic acid to form aboron-functionalized polymer of the present invention. Alternatively,the polyols of the monomers can be esterified with an aryl boronic acidand the resulting boron-functionalized monomer polymerized to form aboron-functionalized polymer of the present invention. Each of thepolyol-containing monomers shown above can be esterified, for example,with any one of the boronic acids shown in FIG. 5.

R and Phenyl Ring B in Structural Formulas (V)-(XI) are as describedabove. R′ in the structures shown above is —H or an alkyl group.

Structural Formula (XII) shows a preferred example of a phenyl boronateester formed from a phenyl boronic acid and an alkyldiol moiety;Structural Formula (XIII) shows a preferred example of a phenyl boronateester formed from a phenyl boronic acid and diethanol amine moiety; andStructural Formula (XIV) shows a preferred example of a phenyl boronateester formed from a phenyl boronic acid and a diethanolammonium moiety:

R₃-R₆ are independently —H or —F; R and R^(e) are as described above.Preferably, R is —CH₂S—(CH₂)_(n)Y, wherein Y and n are as describedabove. In preferred examples, R₃ and R₅ are —F and R₄ and R₆ are —H; andR₃, R₅ and R6 are —H and R₄ is —F.

The present invention also includes polymers comprising one or morephenyl boronate ester group(s) formed from a phenyl boronic acid and analkyldiol, a diethanolamine, or an aminoalkydiol group, e.g., a polymercomprising one or more groups represented by Structural Formula(V)-(XIV).

The term “monomer” refers to both (a) a single molecule comprising oneor more polymerizable functional groups prior to polymerization, or (b)a repeat unit of a polymer. An unpolymerized monomer capable of additionpolymerization, can, for example, comprise an olefinic bond which islost upon polymerization. A “boronate functionalized monomer” is amonomer with a boronate ester group in the side chain that release thecorresponding boronic acid when the ester is hydrolyzed. A “boronatefunctionalized polymer” is a polymer with or formed from boronatefunctionalized monomers that releases the corresponding boronic acidwhen the ester is hydrolyzed.

In a more preferred embodiment, the present invention is a polymercomprising boronate functionalized monomers represented by StructuralFormula (XV):

M is a covalent bond, —CH₂—, 1,3-phenylene, 1,4-phenylene, —C(O)O—,—C(O)NR₁, —C(O)—, —O—, —NR₁—, —CH₂NR₁— or —CH₂O—. Preferably, M is—C(O)NH. Other possible values of M include —N⁺(R₁R₁)— and—CH₂N⁺(R₁R₁)—.

Q is a covalent bond or an inert spacer group. A spacer group serves toseparate the phenyl boronate ester from the polymer. A spacer group is“inert” when it contains no functionality that substantially interfereswith the fat binding ability of the polymer. Inert spacer groups arepreferably hydrocarbyl groups optionally containing one or more linkagegroups and is preferably an alkylene group, preferably C1-C30, morepreferably C1 to C15 and even more preferably C1-C8. Typically, inertspacer groups are hydrophobic.

R₁ is —H, an aliphatic group or a substituted aliphatic group.

R₂ is —H or a C1-C6 alkyl group.

W is a group comprising a phenyl boronate ester formed from a phenylboronic 20 acid and an diethanolamine, an alkyldiol or an aminoalkyldiolgroup, e.g., a group represented by a Structural Formula selected from(V)-(XIV).

In specific examples of boronate functionalized monomers represented byStructural Formula (XV), -MQW comprises a boronate ester formed from—C(O)NH—(CH₂)₂—N—(CH₂CH₂OH)₂, —C(O)NH—(CH₂)₃—N—(CH₂CH₂OH)₂,—C(O)N—(CH₂)₄—N—(CH₂CH₂OH)₂, —C(O)O—(CH₂)₂—N—(CH₂CH₂OH)₂,—C(O)O—(CH₂)₃—N—(CH₂CH₂OH)₂, —C(O)O—(CH₂)₄—N—(CH₂CH₂OH)₂,—NH—(CH₂)₂—N—(CH₂CH₂OH)₂, —NH—(CH₂)₃—N—(CH₂CH₂OH)₂,—NH—(CH₂)₄—N—(CH₂CH₂OH)₂, —O—(CH₂)₂—N—(CH₂CH₂OH)₂,—O—(CH₂)₃—N—(CH₂CH₂OH)₂, —O—(CH₂)₄—N—(CH₂CH₂OH)₂,—CH₂NH—(CH₂)₂—N—(CH₂CH₂OH)₂, —CH₂NH—(CH₂)₃—N—(CH₂CH₂H)₂,—CH₂NH—(CH₂)₄—N—(CH₂CH₂OH)₂, —CH₂CH₂NH—(CH₂)₂—N—(CH₂CH₂OH)₂,—CH₂CH₂NH—(CH₂)₃—N—(CH₂CH₂OH)₂, —CH₂CH₂NH—(CH₂)₄—N—(CH₂CH₂OH)₂, -(1,4-phenylene)CH₂NH—(CH₂)₂—N—(CH₂CH₂OH)₂,-(1,4-phenylene)CH₂NH—(CH₂)₃—N—(CH₂CH₂OH)₂,-(1,4-phenylene)CH₂NH—(CH₂)₄—N—(CH₂CH₂OH)₂,-(1,4-phenylene)NH—(CH₂)₂—N—(CH₂CH₂OH)₂,-(1,4-phenylene)NH—(CH₂)₃—N—(CH₂CH₂OH)₂,-(1,4-phenylene)NH—(CH₂)₄—N—(CH₂CH₂OH)₂,-(1,4-phenylene)O—(CH₂)₂—N—(CH₂CH₂OH)₂,-(1,4-phenylene)O—(CH₂)₃—N—(CH₂CH₂OH)₂,-(1,4-phenylene)O—(CH₂)₄—N—(CH₂CH₂OH)₂,—C(O)NH—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂, —C(O)NH—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂,—C(O)NH—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂, —C(O)O—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂,—C(O)O—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂, —C(O)O—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂,—NH—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂, —NH—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂,—NH—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂, —O—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂,—O—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂, —O—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂,—CH₂NH—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂—CH₂NH—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂,—CH₂NH—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂, —CH₂CH₂NH—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂,—CH₂CH₂NH—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂,—CH₂CH₂NH—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)CH₂NH—(CH₂)₂—N⁺(CH₃)—(CH₂ CH₂OH)₂,-(1,4-phenylene)CH₂NH—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)CH₂NH—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)NH—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)NH—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)NH—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)O—(CH₂)₂—N⁺(CH₃)—(CH₂CH₂OH)₂,-(1,4-phenylene)O—(CH₂)₃—N⁺(CH₃)—(CH₂CH₂OH)₂, or-(1,4-phenylene)O—(CH₂)₄—N⁺(CH₃)—(CH₂CH₂OH)₂ and any one of the boronicacids shown in FIG. 5. Preferred boronic acids are those prepared inExamples 1-10 and variants thereof in which the alkylene group has from5 to 15 carbon atoms. In other specific examples of boronatefunctionalized monomers represented by Structural Formula (XV), -MQWcomprises a boronate ester formed from —C(O)NH—(CH₂)₁CHOHCH₂OH,—C(O)NH—(CH₂)₂CHOHCH₂OH, —C(O)NH—(CH₂)₃CHOHCH₂OH,—C(O)O—(CH₂)₁CHOHCH₂OH, —C(O)O—(CH₂)₂CHOHCH₂OH, —C(O)O—(CH₂)₃CHOHCH₂OH,—NH—(CH₂)₁CHOHCH₂OH, —NH—(CH₂)₂CHOHCH₂OH, —NH—(CH₂)₃CHOHCH₂OH,—O(CH₂)₁CHOHCH₂OH, —O—(CH₂)₂CHOHCH₂OH, —O—(CH₂)₃CHOHCH₂OH,—CH₂NH—(CH₂)₁CHOHCH₂OH, —CH₂NH—(CH₂)₂CHOHCH₂OH, —CH₂NH—(CH₂)₃CHOHCH₂OH,—CH₂CH₂NH—(CH₂)₁CHOHCH₂OH, —CH₂CH₂NH—(CH₂)₂CHOHCH₂OH,—CH₂CH₂NH—(CH₂)₃CHOHCH₂OH, -(1,4-phenylene)CH₂NH—(CH₂)₁CHOHCH₂OH,-(1,4-phenylene)CH₂NH—(CH₂)₂CHOHCH₂OH,-(1,4-phenylene)CH₂NH—(CH₂)₃CHOHCH₂OH,-(1,4-phenylene)NH—(CH₂)₁CHOHCH₂OH, -(1,4-phenylene)NH—(CH₂)₂CHOHCH₂OH,-(1,4-phenylene)NH—(CH₂)₃CHOHCH₂OH, -(1,4-phenylene)O—(CH₂)₁CHOHCH₂OH,-(1,4-phenylene)O—(CH₂)₂CHOHCH₂OH or -(1,4-phenylene)O—(CH₂)₃CHOHCH₂OH,and any one of the boronic acids shown in FIG. 5. Preferred boronicacids are those prepared in Examples 1-10 and variants thereof in whichthe alkylene group has from 5 to 15 carbon atoms.

The polymers of the present invention can be homopolymers, which have auniform backbone composed of a boronate functionalized monomers derivedfrom a common polymerizable unit, such as boronate functionalizedacrylamide. Also included are copolymers and terpolymers, i.e., polymerscomprising a mixed backbone of two or three different monomer units,respectively, one or more of which is boronate functionalized.

“Polymer backbone” or “backbone” refers to that portion of the polymerwhich is a continuous chain, comprising the bonds which are formedbetween monomers upon polymerization. The composition of the polymerbackbone can be described in terms of the identity of the monomers fromwhich it is formed, without regard to the composition of branches, orside chains, off of the polymer backbone. Thus, a poly(acrylamide)polymer is said to have a poly(acrylamide) backbone, without regard tothe substituents on the acrylamide nitrogen atom, which are componentsof the polymer side chains. A poly(acrylamide-co-styrene) copolymer, forexample, is said to have a mixed acrylamide/styrene backbone.

A “side-chain” refers to a branch off of the polymer backbone.

Preferred polymers are “fat binding” polymers. “Fat-binding polymers”are polymers which absorb, bind or otherwise associate with fat therebyinhibiting (partially or completely) fat digestion, hydrolysis, orabsorption in the gastrointestinal tract and/or facilitate the removalof fat from the body prior to digestion. The fat-binding polymerscomprise one or more fat-binding regions. “Fat-binding regions” includea positively charged region, and, optionally, a hydrophobic region, or aregion which is both positively charged and hydrophobic. The fat-bindingregion has a positive charge when the region comprises an ionic groupsuch as a quarternary amine or an atom, for example, the nitrogen of anamine, that possesses a positive charge under conditions present in thegastrointestinal tract. Guidance on preparing and selecting suitablefat-binding polymers can be found in, for example, U.S. Pat. Nos.5,487,888, 5,496,545, 5,607,669, 5,618,530, 5,624,963, 5,667,775, and5,679,717 and co-pending U.S. Applications having Ser. Nos 08/353,329,08/166,453, 08/471,747, 08/482,969, 08/567,933, 08/659,264, 08/823,699,08/835,857, 08/470,940, 08/461,298, 08/826,197, 08/777,408, 08/927,247,08/964,956, 08/964,498, and 08/964,536, the entire contents of all ofwhich are incorporated herein by reference.

The polymers of the present invention include addition polymers such asa boronate functionalized polyacrylate, alkylpolyacrylate,polyacrylamide, alkylpolyacrylamide, poly(allylalcohol),poly(vinylalcohol), poly(vinylamine), poly(allylamine),poly(diallylamine) backbone or a substituted polystyrene backbone.Typically, these addition polymers have side chains comprising arylboronate groups formed from an alkyldiol, a diethanolamine, oraminoalkyldiol and an aryl boronic acid. The side chains are attached,for example, by ester linkages to carboxylate groups of a polyacrylate,by a covalent bond to the amide nitrogens of a polyacrylamide, by etherlinkages to alcohols of a poly(vinylalcohol) or poly(allylalcohol), by acovalent bond to the amines of a poly(vinylamine,) a poly(allylamine) ora poly(diallylamine) or by a covalent bond to a substituent on thephenyl ring of a polystyrene. Polyacrylamide is a preferred polymer.Suitable addition polymers are described below.

In one aspect, the polymer comprises monomers having both cationic andhydrophobic groups. For example, fat-binding polymers of this type canbe a homopolymer, copolymer or terpolymer comprising a boronatefunctionalized monomer with an diethanolamine or aminoalkyldiol in thepolymer side chains, as in Structural Formulas (VIII), (X) and (XII) (orthe corresponding ammonium groups in Structural Formulas (IX), (XI) and(XIV)), provided that the side chain comprises a hydrophobic group(e.g., wherein M in Structural Formula (XV) is a hydrophobic group). Theterm “hydrophobic group” is defined below. The diethanolamine oraminoalkyldiol comprises an amine which can be protonated in vivo toform a cationic group. Another example of a fat-binding polymer of thistype is a copolymer or terpolymer comprising a boronate functionalizedmonomer and a monomer having both cationic and hydrophobic groups.Aliphatic amine monomers in which the amine has at least one hydrophobicalkyl substituent, such as an alkyl group with between about four andthirty carbons, has both a hydrophobic region and a positively chargedregion in combination. Additional aliphatic amine monomers are describedbelow.

In another aspect, the fat-binding polymer comprises boronatefunctionalized monomers together with a combination of separate monomerseach having either a cationic or a hydrophobic functional groups.Examples of monomers having a cationic group and monomers havinghydrophobic groups are provided below.

In another aspect, the fat-binding polymer comprises monomers havingboth cationic and neutral functional groups (e.g., a hydroxy group or acarboxamide group). Fat-binding polymer of this type includehomopolymers, copolymers or terpolymers comprising a boronatefunctionalized monomer with a diethanolamine or an aminoalkyldiol in thepolymer side chains, as in Structural Formulas (VIII), (XI) and (XIII)(or the corresponding ammonium groups in Structural Formulas (IX), (XI)or (XIV). The aminoalkyldiol comprises an amine which can be protonatedin vivo and diols which are released when the boronate ester ishydrolyzed. Alternatively, the fat-binding polymer of this type is aco-polymer or terpolymer comprising a boronate functionalized monomerand a monomer have both a neutral and a cationic functional group.Examples of monomers of this type include aliphatic amine monomerswherein the amine group is derivatized with a hydroxy alkyl group (e.g.,N-(ω-hydroxyalkyl)allylamine and N-(ω-hydroxyalkyl)vinylamine).

Alternatively, the fat-binding polymer comprises a combination ofseparate monomers each having either a cationic or a neutral functionalgroup. As noted above, hydrolysis in the gastrointestinal tract of thephenyl boronate ester of a boronate functionalized monomer “releases” adiol functionality. Thus, fat-binding polymers of this type includecopolymers comprising a boronate functionalized monomer and a cationicmonomer such an aliphatic amine monomer. In another example, thefat-binding polymer is a terpolymer comprising a boronate functionalizedmonomer, a cationic monomer (e.g., an aliphatic amine monomer) and aneutral co-monomer(e.g., vinyl alcohol, allyl alcohol and acrylamide).

Cationic monomers include monomers which contain amine groups, i.e.,“amine monomers”. Specific examples of aliphatic amine monomers found inaddition polymers include allylamine, diallylamine, diallylmethylamineand vinylamine. Other amine monomers include aminostyrene,vinylimidazolyl, vinylpyridinyl, dimethylaminomethylstyrene anddiallylmethylammonium chloride. Yet other examples of amine monomersinclude amine or quaternary amine-containing moieties used inconjunction with acrylate or acrylamide polymers. Examples includeaminoalkyl esters or ammoniumalkyl (e.g., trialkylammonium alkyl) estersof an acrylate monomer (e.g., trimethylammonium ethyl methacrylate andtrimethylammonium ethyl acrylate) or N-aminoalkyl amide orN-ammoniumalkyl amides (e.g., N-trialkylammonium alkyl) of acrylamides(e.g., N-trimethylammonium ethyl methacryamide and N-trimethylammoniumethyl acrylamide).

As noted above, an amine monomer can comprise one or more hydrophobicregions which are bound to the amine nitrogen of the amine monomer toform a monomer with both a cationic and hydrophobic group. Examplesinclude N-(C4-C30)alkylvinylamine, N-(C4-C30)alkylallylamine,N-(C4-C30)alkyldiallylamine, N-(C4-C30)alkylaminostyrene andN,N-(C1-C30)dialkylaminostyrene.

Hydrophobic monomers are monomers which lack a cationic group andcomprise a hydrophobic group. Examples include styrene, (C6-C30)olefinic monomers (e.g., hexene, heptene, octene),(C4-C30)alkylacrylates, (C4-C30)alkylmethacrylates,N-(C4-C30)alkylacrylamides, N-(C4-C30)alkylmethacrylamides, styrene(e.g., fluorstyrene and pentaflourostyrene), vinylnaphthalene,ethylvinylbenzene, vinylbiphenyl, vinylanisole.

Optionally, fat-binding polymers can comprise hydrophilic monomers.Examples include acrylic acid, methacrylic acid, acrylamide andmethacrylamide.

The present invention also includes condensation polymers, which areformed from reactions in which a small molecule such as water isreleased. Examples include a polyamide, polyalkyleneimine or apolyester. The cationic groups in a polyalkyleneimine can be the amineor ammonium nitrogens in the backbone or, alternatively ammoniumalkyl(e.g., a trialkylammonium alkyl group) or hydroxylated alkyl (e.g.,hydroxyethyl) bonded to nitrogen in the polymer backbone or an aminegroup in the side chain connecting the boronate ester to a nitrogen inthe backbone. The hydrophobic group can be a C4-C30 alkylene group inthe polymer backbone, a hydrophobic alkyl group bonded to a backbonenitrogen atom or a hydrophobic spacer group Q, between nitrogen in thebackbone and W, wherein Q and W are as defined above. For polyamides, agroup -Q-W can be bonded to amide nitrogens in the polymer backbone,wherein Q and W are as defined above and are selected such that Q ishydrophobic and W comprises a diethanolamine or an aminoalkyldiol or thecorresponding ammonium compounds, as shown in Structural Formulas(V)-(XIV). For polyesters, a group -Q-W can be bonded to a carbon atomin the backbone wherein Q and W are as defined above and are selectedsuch that Q is hydrophobic and W comprises a diethanolamine or anaminoalkyldiol or the corresponding ammonium compounds, as shown inStructural Formulas (V)-(XIV).

The polymer can be linear or crosslinked. Crosslinking can be performedby reacting the copolymer with one or more crosslinking agents havingtwo or more functional groups, such as electrophilic groups, which reactwith, for example, amine groups to form a covalent bond. Crosslinking inthis case can occur, for example, via nucleophilic attack of the polymeramino groups on the electrophilic groups. This results in the formationof a bridging unit which links two or more amino nitrogen atoms fromdifferent polymer strands. Suitable crosslinking agents of this typeinclude compounds having two or more groups selected from among acylchloride, epoxide, and alkyl-X, wherein X is a suitable leaving group,such as a halo, tosyl or mesyl group. Examples of such compoundsinclude, but are not limited to, epichlorohydrin, succinyl dichloride,acryloyl chloride, butanedioldiglycidyl ether, ethanedioldiglycidylether, pyromellitic dianhydride, and dihaloalkanes. These crosslinkingagents are referred to herein as multifunctional crosslinking agents.

The polymer composition can also be crosslinked by including amultifunctional co-monomer as the crosslinking agent in thepolymerization reaction mixture. A multifunctional co-monomer can beincorporated into two or more growing polymer chains, therebycrosslinking the chains. Suitable multifunctional co-monomers include,but are not limited to, diacrylates, triacrylates, and tetraacrylates,dimethacrylates, diacrylamides, and dimethacrylamides. Specific examplesinclude ethylene glycol diacrylate, propylene glycol diacrylate,butylene glycol diacrylate, ethylene glycol dimethacrylate, butyleneglycol dimethacrylate, methylene bis(methacrylamide), ethylenebis(acrylamide), ethylene bis(methacrylamide), ethylidenebis(acrylamide), ethylidene bis(methacrylamide), pentaerythritoltetraacrylate, trimethylolpropane triacrylate, bisphenol Adimethacrylate, and bisphenol A diacrylate. Other suitablemultifunctional monomers include polyvinylarenes, such asdivinylbenzene.

The amount of cross-linking agent is typically between about 0.01 andabout 10 weight % based on the combined weight of crosslinking agent andmonomers, with 0.1-3% being preferred. Typically, the amount ofcross-linking agent that is reacted with the polymer, when thecrosslinking agent is a multifunctional agent, is sufficient to causebetween about 0.1 and 6 percent of the nucleophiles present on themonomer, for example, an amine to react with the crosslinking agent.

In addition, the polymers can be further characterized by one or moresubstituents such as substituted and unsubstituted, saturated orunsaturated alkyl, and substituted or unsubstituted aryl groups.Suitable groups to employ include cationic or neutral groups, such asalkoxy, aryl, aryloxy, aralkyl, halogen, amine, ammonium groups,substituted or unsubstituted oxypolyethylene oxide, and mono, di orhigher hydroxyalkyl groups.

A “hydrophobic moiety (group)”, as the term is used herein, is a moietywhich, as a separate entity, is more soluble in octanol than water. Forexample, the octyl group (C₈H₁₇) is hydrophobic because its parentalkane, octane, has greater solubility in octanol than in water. Thehydrophobic moieties can be a saturated or unsaturated, substituted orunsubstituted hydrocarbon group. Such groups include substituted andunsubstituted, normal, branched or cyclic alkyl groups having at leastfour carbon atoms, substituted or unsubstituted arylalkyl orheteroarylalkyl groups and substituted or unsubstituted aryl orheteroaryl groups. Preferably, the hydrophobic moiety includes an alkylgroup of between about four and thirty carbons. Specific examples ofsuitable hydrophobic moieties include the following alkyl groupsn-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tetradecyl, n-octadecyl, 2-ethylhexyl, 3-propyl-6-methyl decyl, phenyland combinations thereof. Other examples of suitable hydrophobicmoieties include haloalkyl groups of at least six carbons (e.g.,10-halodecyl), hydroxyalkyl groups of at least six carbons (e.g.,11-hydroxyundecyl), and aralkyl groups (e.g., benzyl).

A “hydrophobic alkyl group”, as that term is employed herein, includes asubstituted or unsubstituted alkyl group having from four to aboutthirty carbons and which is hydrophobic, as earlier defined. Thehydrophobic alkyl group can be, for example, normal or branched.

As used herein, aliphatic groups include straight chained, branched orcyclic C1-C30 (preferably C5-C22) hydrocarbons which are completelysaturated or which contain one or more units of unsaturation. Preferredaliphatic groups are completely saturated and acyclic, i.e., straightchained or branched alkyl groups. Suitable substituents for an aliphaticgroup are those which do not significantly lower the lipase inhibitingability or fat binding ability of the polymer, for example, do not lowereither activity by more than a factor of about two. Examples include—OH, halogen (—Br, —Cl, —I and —F), —O(R′), —O—CO—(R′), —CN, —NO₂,—COOH, ═O, —NH₂, —NH(R′), —N(R′)₂, —COO(R′), —CONH₂, —CONH(R′),—CON(R′)₂, —SH and —S(R′). Each R′ is independently an alkyl group or anaryl group. A substituted aliphatic group can have more than onesubstituent.

Aryl groups include carbocyclic aromatic groups such as phenyl andnaphthyl, heteroaryl groups such as imidazolyl, thienyl, furanyl,pyridyl, pyrimidy, pyranyl, pyrazolyl, pyrazinyl, thiazole, oxazolyl andfused polycyclic aromatic ring systems in which a carbocyclic aromaticring or heteroaryl ring is fused to one or more other heteroaryl rings(e.g., benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazole,benzooxazole, benzimidazole and quinolinyl). Suitable substituents foran aryl group are those which do not significantly lower the lipaseinhibiting ability or fat binding ability of the polymer, for example,do not lower either activity by more than a factor of about two.Examples include alkyl, halogenated alkyl, —OH, halogen (—Br, —Cl, —Iand —F), —O(R′), —O—CO—(R′), —CN, —NO₂, —COOH, —NH₂, —NH(R′), —N(R′)₂,—COO(R′), —CONH₂, —CONH(R′), —CON(R′)₂, —SH and —S(R′). Each R′ isindependently an alkyl group or an aryl group. A substituted aryl groupcan have more than one substituent.

Non-aromatic nitrogen-containing, heterocyclic rings are non-aromaticcarbocyclic rings which include at least one nitrogen atom and,optionally, one or more other heteroatoms such as oxygen or sulfur inthe ring. The ring can be five, six, seven or eight-membered. Examplesinclude morpholino, thiomorpholino, pyrrolidinyl, piperazinyl andpiperidinyl.

In the structural formulas depicted herein, the single or double bond bywhich a chemical group or moiety is connected to the remainder of themolecule or compound is indicated by the following symbol:

For example, the corresponding symbol in Structural Formulas (I) and(II) boronate ester bond by which the phenylboronate group is connectedto the polymer.

Also included in the present invention are pharmaceutically acceptablesalts of the disclosed polymers. For example, polymers which have acidfunctional groups can also be present in the anionic, or conjugate base,form, in combination with a cation. Suitable cations include alkalineearth metal ions, such as sodium and potassium ions, alkaline earthions, such as calcium and magnesium ions, and unsubstituted andsubstituted (primary, secondary, tertiary and quaternary) ammonium ions.Polymers which have basic groups such as amines can also be protonatedwith a pharmaceutically acceptable counter anion, such as chloride,bromide, acetate, formate, citrate, ascorbate, sulfate or phosphate.Similarly, ammonium groups similarly comprise a pharmaceuticallyacceptable counteranion. Boronic acid groups can react with anions suchas sodium or potassium hydroxide, alkoxide or carboxylate to form a saltsuch as —B⁻(OH)₃Na⁺, —B⁻(OH)₃K⁺, —B⁻(OH)₂(OCH₃)Na⁺, —B⁻(OH)₂(OCH₃)K⁺,—B⁻(OH)₂(OCOCH₃)Na⁺, —B⁻(OH)₂(OCOCH₃)K⁺, and the like

The positive charge of ammonium groups in the disclosed polymers arecounterbalanced with a suitable counteranion such as Cl⁻, Br⁻, I⁻, NO₃⁻, HSO₄ ⁻, CO₃ ^(−2,) HCO₃ ⁻ or SO₄ ⁻². The counteranions on a polymercan be the same or different. An anion with a charge greater than onewill counterbalance the positive charge of more than one ammonium group.

A “subject” is preferably a mammal, such as a human, but can also be acompanion animal (e.g., dogs, cats, and the like), farm animals (e.g.,cows, sheep, pigs, horses, and the like) or laboratory animals (e.g.,rats, mice, guinea pigs, and the like) in need of treatment for obesity.

The polymers of the present invention are suitable as a medicament forpromoting weight reduction in mammals because they inhibit lipases andbind fat molecules such as diglycerides and triglycerides, in thegastrointestinal tract. As such, they are administered in a mannersuitable for reaching the gastrointestinal tract during digestion. Theyare therefore preferably administered orally as soon as up to about onehour prior to a meal and as late as to up to about one hour subsequentto a meal. Preferably, the polymer of sufficiently high molecular weightto resist absorption, partially or completely, from the gastrointestinaltract into other parts of the body. The polymers can have molecularweights ranging from about 500 Daltons to about 500,000 Daltons,preferably from about 2,000 Daltons to about 150,000 Daltons. In thepolymers represented herein by structural formulas, e.g., StructuralFormula (XV), “n” represents an integer chosen such that the polymer hasthe desired molecular weight.

The polymers of the present invention are administered to inhibit ofuptake of fat in the gastrointestinal tract (or to promote removal offat from the gastrointestinal tract). Thus, they can be also beadvantageously used to in the treatment or one or more of the followingconditions: obesity, Type II (non-insulin-dependent) diabetes mellitus,impaired glucose tolerance, hypertension, coronary thrombosis, stroke,lipid syndromes, hyperglycemia, hypertriglyceridemia, hyperlipidemia,sleep apnea, hiatal hernia, reflux esophagisitis, osteoarthritis, gout,cancers associated with weight gain, gallstones, kidney stones,pulmonary hypertension, infertility, cardiovascular disease, abovenormal weight, and above normal lipid levels; or where the subject wouldbenefit from reduced platelet adhesiveness, weight loss after pregnancy,lowered lipid levels, lowered uric acid levels, or lowered oxalatelevels. A subject with one or more of these conditions is said to be “inneed of treatment” with an agent that inhibits absorption of fat fromthe gastrointestinal tract.

An “effective amount” is the quantity of polymer which results in agreater amount of excretion of fat from the gastrointestinal tract overa period of time during which a subject is being treated with thepolymer drug compared with the corresponding time period in absence ofsuch treatment. When the subject is being treated for obesity, an“effective amount” is the quantity of polymer which results in a greateramount of weight reduction over a period of time during which a subjectis being treated with the polymer drug compared with the correspondingtime period in absence of such treatment. Typical dosages range fromabout 5 milligrams/day to about 10 grams/day, preferably from about 50milligrams/day to about 5 grams/day. The polymer can be administeredalone or in a pharmaceutical composition comprising the polymer, anacceptable carrier or diluent and, optionally, one or more additionaldrugs, typically one or more additional drugs used for weight reduction(e.g., XENICAL or MERIDIA). Typically, the pharmaceutical compositioncomprises an effective concentration of the polymer, which is aconcentration which can administer an effective amount of the polymer.

The precise amount of polymer being administered to a subject will bedetermined on an individual basis and will depend on, at least in part,the subject's individual characteristics, such as general health, age,sex, body weight and tolerance to drugs, and the degree to which thesubject is overweight and the amount of weight reduction sought.

The disclosed polymers can be administered to the subjects inconjunction with an acceptable pharmaceutical carrier as part of apharmaceutical composition for treatment of obesity. Formulations varyaccording to the route of administration selected, but for oraladministration are typically capsule. Solutions and emulsions are alsopossible. Suitable pharmaceutical carriers may contain inert ingredientswhich do not interact with the compound. Standard pharmaceuticalformulation techniques can be employed, such as those described inRemington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa. s for encapsulating compositions (such as in a coating of hardgelatin or cyclodextran) are known in the art (Baker, et al.,“Controlled Release of Biological Active Agents”, John Wiley and Sons,1986).

The polymer of the present invention can be prepared by synthesizingmonomer comprising side chains with diethanol amine alkyldiol oraminoalkyldiol groups, as is described, for example, in Example 11 andshown schematically in FIG. 4, and then polymerizing. A suitable arylboronic acid is prepared and then coupled to the diol groups in thepolymer product. Alternatively, boron functionalized monomers areprepared and then polymerized according to standard means.

The polymerization includes direct polymerization of a diethanol aminealkyldiol or aminoalkyldiol functionalized monomer (or boronfunctionalized) or with a set of monomers, one of which isdiethanolamine, alkyldiol or aminoalkyldiol functionalized (or boronfunctionalized). This can be accomplished via standard s of freeradical, cationic or anionic polymerization which are well known in theart. Due to reactivity differences between two monomers, the compositionof a copolymer produced in this way can differ from the composition ofthe starting mixture. This reactivity difference can also result in anon-random distribution of monomers along the polymer chain.

The preparation of representative phenyl boronic acid compounds isdescribed in Examples 1-10 and shown schematically in FIGS. 1-3. Theperson of ordinary skill in the art will be able to select suitablestarting materials to obtain the desired aryl boronic acid and, whencarrying out these reactions with different starting materials to modifyreaction conditions, if necessary, using no more than routineexperimentation. For example, the 4-bromoacetophenone in FIG. 2(Compound 7) can be replaced with any suitable aryl compound substitutedwith bromine or iodine and acetyl. For example,2-Acetyl-5-bromothiophene is commercially available from the AldrichChemical Co., Milwaukee, Wis. The length of the hydrocarbyl group in thearyl boronic acids can be varied according to the length of the1,ω-alkanethioalcohol.

Representative boronic acids of the present invention that have beenprepared according to s described in the examples are shown in FIG. 5.

The preparation of diethanolamino functionalized polymers is describedin Example 11 and shown schematically in FIG. 4.

The esterification of diol groups with aryl boronic acids can be carriedout be s known in the art, for example, by reacting in suitable solvent,e.g., alcohol, toluene, methylene chloride, tetrahydrofuran ordimethylsulfoxide. Specific conditions are provided in Example 12.Analogous conditions can be used to esterify diol groups in monomerscomprising diethanolamine, alkyldiol or aminoalkyldiol side chains.Alternatively, a transesterification reaction can be used to prepare aboronate ester from a boronic acid and polymer comprising adiethanolamine, alkyldiol or aminoalkyldiol side chains, for example, asis disclosed in D. H. Kinder and M. M. Ames, Journal of OrganicChemistry 52:2452 (1987) and D. S. Matteson and R. Ray, Journal ofAmerican Chemical Society 102:7590 (1980). The entire teachings of thesereferences are incorporated herein by reference.

The invention is further illustrated by the following examples which arenot intended to be limiting in any way.

EXEMPLIFICATION Example 14-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid chloride (6)

The synthesis of Compound (6) is shown out schematically in FIG. 1. Adetailed description of the procedure is provided below.

Step 1. Synthesis of 4-acetyl-3-fluorophenylboronic acid (1)

An oven-dried, 3-liter, 3-necked, round-bottomed flask (fitted with anitrogen inlet, addition funnel, and overhead stirrer) was charged with50 grams (0.25 mole) of 4-cyano-3-fluorophenyl bromide. Anhydroustetrahydrofuran (200 milliliters) was added to the flask resulting in aclear solution. The solution was cooled to 0° C. using an ice bath. Atthis temperature, 125 milliliters of 3.0 M solution of CH₃MgBr in ether(1.5 equivalents, 0.375 mole) was added slowly to the reaction flaskusing an addition funnel. The reaction mixture was allowed to slowlywarm up to room temperature and was stirred for 48 hours. Thin layerchromatography (TLC) indicated the starting material was consumed. After48 hours, the reaction was cooled down to −78° C. using anisopropanol/dry ice bath. At −78° C., 50 milliliters of 10.0 M solutionof butyllithium in hexane (2.0 equivalents, 0.5 mole) was added to thereaction mixture with continuing stirring. An additional 400 millilitersof THF was added to ensure that reaction mixture was homogeneous and wasstirring well. The reaction mixture was stirred at −78° C. for 3 hours.To the reaction mixture was added 170 milliliters of trimethylborate(6.0 equivalents, 1.5 mole) slowly using an addition funnel and thetemperature was maintained at −78° C. While stirring, the reactionmixture was allowed to warm up to room temperature overnight. Theprogress of the reaction was monitored by TLC. After cooling thereaction mixture to 0° C. (using an ice bath) the contents weretransferred into a 5 liter beaker. The flask was rinsed with 100milliliters of methanol and the washing was combined with the reactionmixture. To the reaction mixture, 500 milliliters of 1 N HCl was slowlyadded. Subsequently, the pH of the mixture was brought to 4 by theaddition of concentrated HCl. The reaction mixture was stirred for 3hours. The organic solvent was removed by rotary evaporator. Theconcentrated aqueous content was extracted with ether (250milliliter×6). The combined organic layer was washed with brine solution(200 milliliter×2) and was dried over MgSO₄. After filtration, ether wasremoved by rotary evaporator. The residue was recrystallized from hotwater yielding an off white solid. Yield: 22 grams (50%).

Step 2. Synthesis of 4-(2′-bromoacetyl)-3-fluorophenylboronic acid (2)

An oven-dried, 500-milliliter, 3-necked, round-bottomed flask wascharged with 5 grams (27.4 millimole) of 4-acetyl-3-fluorophenyl boronicacid and 25 milliliters of methanol under a nitrogen atmosphere. Thesolution was cooled to 0° C. using an ice bath. To this solution wasadded 0.2 milliliters (0.55 equivalents) of glacial acetic acid. In a100 milliliters Erlenmeyer flask was taken 1.27 milliliters (3.95 grams,24 millimole, 0.9 equivalents) of elemental bromine dissolved in 4milliliters of cold methanol. The bromine solution was added dropwise tothe above solution at 0° C. using an addition funnel. With the additionof Br₂, the solution slowly turned light orange and finally to darkorange when addition was complete. After about 5-6 hours, the progressof the reaction was monitored by NMR. Depending on the progress ofreaction, another 10-20 mole % of bromine was added after cooling thesolution to 0° C. Total reaction time was approximately 24 hours.

After completion of the reaction, the solvent was removed using rotaryevaporator. The residue was dissolved in 200 milliliters of ethylacetate. It was washed with deionized water (50 milliliters×3) and withbrine (50 milliliters×2). The organic layer was collected and dried overanhydrous sodium sulfate for 1 hour. The solution was filtered and thesolvent was removed using rotary evaporator. The residue wasrecrystallized from hot ethyl acetate. Yield=7 grams (97%).

Step 3. Synthesis of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid (3)

An oven-dried, 500-milliliter, three-necked, round-bottomed flask wascharged with 5 grams (19.15 millimole) of4-(2′-bromoacetyl)-3-fluorophenylboronic acid (2) and 50 milliliters ofanhydrous THF. The solution was flushed with N₂ for at least 30 minutes.To this solution was added 3.9 grams (19.15 millimole, 1 equivlalent) of11-mercaptoundecanol. While stirring under N₂, 6.62 milliliters (38.3millimole, 2 equivalents) of diisopropylethylamine was added slowly. Thereaction mixture was stirred at room temperature for 24 hours undernitrogen atmosphere. The progress of the reaction was monitored by TLCand NMR (after washing up the aliquot with 1 N HCl). If the reaction wasnot complete, additional (as required) 11-mercaptoundecanol was addedand the reaction was allowed to proceed for another 24 hours. Aftercompletion of the reaction, the solvent was evaporated. The residue wasdissolved in 200 milliliters of ethyl acetate and was washed with water(50 milliliters×3), 1 N HCl (50 milliliters×3) and with brine (50milliliters×2). The organic layer was dried over an anhydrous sodiumsulfate for 1 hour. After filtration, the solvent was removed by rotaryevaporator. The residue was recrystallized from ethyl acetate. Yield: 5grams (72%).

Step 4. Synthesis of neopentyl glycol protected4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid (4)

An oven-dried, 500-milliliter, 3-necked, round-bottomed flask wascharged with 5 grams (13 millimole) of 3 as prepared above. Addition of100 milliliters of anhydrous dichloromethane produced a dispersion.While stirring, 1.42 grams (13.65 millimoles, 1.05 equivalents) ofneopentylglycol was added to this dispersion. After few minutes a clearsolution was obtained. The stirred reaction mixture was heated toreflux. A chiller and a Dean Stark apparatus were used to remove thedichloromethane-water azeotrope. The heating continued for about 3hours.

At the end of reflux, the reaction mixture was allowed to cool to roomtemperature and the solvent was removed using a rotary evaporator.Anhydrous toluene (50 milliliters) was added to the residue and thetoluene was removed using a rotary evaporator. This toluene treatmentprocess was repeated once more. The residue was dissolved in 5milliliters of dichlormethane, and hexane was added to this solution(with stirring) until cloudiness appeared (about 150 milliliters). Thesolution was kept in the freezer for recrystallizaton. After few hoursthe product crystallized and was isolated by filtration. Yield =5.13grams (87%).

Step 5. Synthesis of neopentyl glycol protected4-(14′-bromo-3′-thia-1-ketotetradecyl)-3-fluorophenylboronic acid (5)

The reaction was carried out under N₂ atmosphere.

An oven-dried, 500-milliliter, 3-necked, round-bottomed flask wascharged with 5.13 grams (11.33 millimole) of the neopentyl glycolprotected boronic acid (4) and 50 milliliters of anhydrousdichloromethane under a nitrogen atmosphere. To this solution was added7.52 grams (22.67 millimole, 2 equivalents) of carbon tetrabromide. Theresulting solution was allowed to stir at 0° C. using an ice bath. Asolution of 5.95 grams (22.67 millimole, 2 equivalents) oftriphenylphosphine dissolved in 10 milliliters of anhydrousdichloromethane was added slowly to the reaction mixture using anaddition funnel. The reaction mixture was stirred at 0° C. and wasallowed to slowly warm to room temperature. Total reaction time wasabout 24 hours. At the end of the reaction 20 milliliters of methanolwas added to the reaction mixture. After stirring for 1 hour, thesolvent was removed by rotary evaporator. The residue was treated with200 milliliters of diethyl ether and stirred for 30 minutes. The mixturewas filtered and the solvent was removed under reduced pressure. Theresidue was given another ether treatment in the above manner and thesolvent was removed. The resulting residue was flash chromatographedusing hexane/ethyl acetate (98/2) as the solvent system. After removalof the solvent the product was isolated as an off-white solid. Yield=4.3grams (74%).

Step 6. Synthesis of4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid chloride (6)

A 100-milliliter, round-bottomed flask was charged with 4.3 grams (8.3millimole) of boronic acid derivative (5) and 40 milliliters of ethanol.To this solution was added 40 milliliters of aqueous trimethylaminesolution (40%, Aldrich). The reaction mixture was stirred at 70° C. for24 hours. After cooling to room temperature, the ethanol was removed byrotary evaporator. The remaining aqueous solution was cooled to 0° C.and 180 milliliters of 1 N HCl was added slowly into the stirringsolution. If precipitation occurs, some methanol is added until a clearsolution forms. After stirring for 5 hours, the solution (turbid) wasextracted with chloroform (3×200 milliliters). Organic layers werecollected and dried over sodium sulfate. The chloroform was evaporatedand the residue was dissolved in methanol (20 milliliters). Sodiumchloride solution (10% w/w, 200 milliliters) was added to the methanolsolution and stirred for 1 hour. At this point, the organic solvent wasremoved using rotary evaporator and compound was extracted from aqueoussolution with chloroform (3×200 milliliters). Organic layers werecollected and dried over sodium sulfate. After filtration, the solventwas removed using rotary evaporator. The residue was added to 600milliliters of ether and the mixture was kept in the freezer for 3hours. The solvent was decanted to isolate the product. Yield=2 grams.

Example 2 Synthesis of2,5-difluoro-4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(11)

The synthesis of Compound (11) is shown out schematically in FIG. 2. Adetailed description of the procedure is provided below.

Step 1—Synthesis of 4-bromo-2,5-difluoroacetophenone (7)

Anhydrous aluminum chloride was mixed (5 grams, 37.5 millimoles, 2.4equivalents) with 1-bromo-2,5 difluorobenzene in a dry, round-bottomflask blanketed with nitrogen and fitted with a condenser. The mixturewas heated to 60° C. and acetyl chloride (1.7 milliliters, 23.3millimole, 1.5 equivalents) was added by syringe. The wet yellow solidchanged then into a scarlet solution and was heated at 90° C. for 1hour. The reaction mixture was poured onto 38 grams of ice, HCl wasadded (3 milliliters, 37% concentration) and the mixture was extractedwith ether. The crude material was dried over magnesium sulfate andevaporated down. The crude material was purified by columnchromatography or distilled. The product (1.2 grams, 31%) was obtainedas a yellow oil.

Step 2—Synthesis of neopentyl glycol protected4-acetyl-2,5-difluorofluorophenylboronic acid (8)

Dichloro [(1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (1.7 grams, 2.3 millimole, 5% mole) was added toa suspension of 4-bromo-2,5 difluoroacetophenone (7) (10.5 grams, 46.38millimole, 1 equivalents), bis(neopentyl glycolato)diboron (12.57 grams,55.65 millimole, 1.2 equivalents) and potassium acetate (13.66 grams,139.13 millimole, 3 equivalents) in anhydrous DMSO (100 milliliters).The suspension was heated to 80° C. under nitrogen for 1 hour (J. Org.Chem. 60:7508 (1995)). After 1 hour, TLC showed full conversion of thestarting material and the reaction mixture was allowed to cool down andextracted with toluene, washed three times with water and dried overmagnesium sulfate. Flash column chromatography was used to purify thecrude (4.2 grams, 32%).

Step 3—Synthesis of neopentyl glycol Protected4-(2′-bromoacetyl)-2,5-difluorophenylboronic acid (9)

The boronic ester (8) (4.1 grams, 14.93 millimole, 1 equivalent) wasdissolved in methylene chloride (50 milliliters) and cooled down to −10°C. Acetic acid (0.82 milliliters, 14.32 millimole, 1 equivalent) wasadded, followed by bromine (0.7 milliliters, 13.4 millimole, 0.9equivalents) and the reaction was warmed up to room temperature. Afterstirring for two hours the reaction mixture was diluted with moremethylene chloride and washed once with water and once with brine. Thecrude was dried over magnesium sulfate, evaporated down and used in thenext step without further purification.

Step 4—Synthesis of neopentyl glycol Protected2,5-difluoro-4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(10)

Crude Compound (9) (14.93 millimole) was dissolved in anhydrous methanol(50 milliliters) and nitrogen gas was bubbled into the solution for 20minutes to degas the mixture. 1 1-mercaptoundecanol (3.1 grams, 14.93millimole, 1 equivalent) was added to the reaction and the solution wasallowed to stir under nitrogen for five minutes before adding anhydrousdiisopropylamine (5.2 milliliters, 29.9 millimole, 2 equivalents). Thereaction was left to stir under nitrogen overnight and the crude wasworked up by evaporating the reaction mixture to dryness andre-dissolving it in a 10% mixture of THF in ethyl acetate (100milliliters). This organic layer was then washed with 200 milliliters ofwater and the aqueous layer was separated and washed with three newfractions of the same THF/ethyl acetate mixture (100 milliliters each).The crude organic layers were combined, dried over magnesium sulfate andevaporated down. Flash chromatography was used to purify the crude andan off white solid was obtained (3.5 grams, 50%).

Step 5—Synthesis of2,5-difluoro-4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(11)

De-protection of the neopentyl group in Compound (10) to give Compound(11) was carried out by dissolving Compound (10) in methanol and addinga few drops of HCl. After stirring for about an hour the crude productwas concentrated on a rotary evaporator and the final compound wasrecrystallized from hot ethyl acetate.

Example 3 Synthesis of2,5-difluoro-4-(13′-trimethylamonium-3′-thia-1′-ketotridecyl)phenyl(neopentylglycolato) boron chloride (14)

The synthesis of Compound (14) is shown schematically in FIG. 3. Adetailed description of the procedure is provided below.

Step 1—Synthesis of 10-bromodecyltrimethylammonium bromide

1,10-Dibromodecane (20 grams, 66.7 mmoles) and THF (100 milliliters)were placed in a 500-mL, three-necked flask. The solution was cooled to0° C. with an ice-water bath. Anhydrous trimethylamine (3 grams, 50.8mmoles) was added to the mixture by slowly bubbling trimethylamine gasfor about 15 minutes. Then the reaction mixture was allowed to warm toroom temperature and stirred at room temperature overnight. The solidmaterial was filtered and washed with THF (5×30 milliliters). Afterdrying in vacuo overnight, 12.5 grams (34.82 mmoles, 69% based on theamine used) of the product was obtained as a white solid.

Step 2—Synthesis of 10-mercaptodecyltrimethylammonium bromide

10-Bromodecyltrimethylammonium bromide (10 grams, 27.9 mmoles) in 50 mLof methanol was placed in a 250-milliliter, three-necked flask. Themixture was degassed vigorously by bubbling nitrogen for 30 minutes.Potassium thioacetate (3.8 grams, 33.5 mmoles, 1.2 equivalents) wasadded to the reaction mixture. The mixture was heated at 50° C. for 12hours under nitrogen. The reaction mixture was cooled to 0° C. with anice-water bath, degassed sodium hydroxide (50%, 2.7 grams, 33.5 mmoles,1.2 equivalents) was added, and the mixture was stirred for 1 h at roomtemperature. The mixture was cooled to 0° C., and degassed concentratedhydrochloride acid was added dropwise to achieve pH 2. Degassed methanol(100 milliliters) was added to the reaction mixture, followed by theaddition of 40 grams of magnesium sulfate. Magnesium sulfate wasfiltered off and washed with methanol. The methanol solution wasconcentrated to about 20 milliliters, and ether (300 milliliters) wasadded to the mixture. The flask was sealed and placed in a freezer.Product was crystallized out as a white solid. The product was filtered,washed with ether, and dried in vacuo. Product (7.5 grams, 24.0 mmoles,86%) was obtained as a white hydroscopic solid.

Step 3—Synthesis of2,5-difluoro-4-(13′-trimethylammonium-3′-thia-1′-ketotridecyl)fluorophenylboronicacid bromide

4-(2′-Bromoacetyl)-2,5-difluorophenyl (neopentyl glycolato) boron(Compound 9) (1 millimole) was dissolved in anhydrous methanol (10milliliters) and nitrogen gas was bubbled into the solution for 20minutes to degas the mixture. 10-mercaptodecyltrimethylammonium bromide(0.19 grams, 0.8 millimole, 0.8 equivalents) was added to the reactionand the solution was stirred under nitrogen for five minutes beforeadding anhydrous diisopropylamine (0.14 milliliters, 1 millimole, 1equivalent). The reaction was stirred under nitrogen overnight and,after concentration on a rotary evaporator, purified by preparativereversed phase PLC.

Example 4 Synthesis of4-(14′-trimethylammonium-3′-thia-1′-keto-tetradecyl)phenylboronic acidchloride

Step 1. Synthesis of 4-(2′-Bromoacetyl)phenylboronic acid

An oven-dried, two liter, three-necked, round-bottomed flask was chargedwith 4-acetyl-phenylboronic acid (20 grams, 0.152 mole). While stirring,175 ml of THF were added to the reaction mixture, followed by 700 ml ofchloroform. To the resulting solution was added 5 ml of glacial aceticacid. A chloroform solution of bromine (prepared by dissolving 7 ml ofbromine in 30 ml of chloroform) was added slowly to the reaction mixtureat about 5° C. After the completion of the addition of bromine, thereaction mixture was allowed to warm to room temperature and stirred atroom temperature for 16 hours. The solvent was removed by rotaryevaporation and the residue was dissolved in 1 liter of ethyl acetate.The resulting solution was extracted with deionized water (3×200 ml) andbrine (2×100 ml). The organic layer was dried over anhydrous sodiumsulfate for 1 hour. The solution was then filtered and concentrated toabout ⅓ of its volume. The resulting solution was kept in a freezer tocrystallize the product. The solid was filtered to give an off whitesolid. Yield=16 grams

Step 2. 4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid

A 500-ml, three-necked, round-bottomed flask was charged with 15 gramsof 4-(2′-bromoacetyl)phenylboronic acid and 300 ml of anhydrous THF.While stirring under a nitrogen atmosphere, 12.26 grams of11-mercaptoundecanol were added to the reaction mixture, followed by32.35 ml of diisopropylethylamine. The reaction mixture was stirredunder a nitrogen atmosphere for 48 hours. After removing the solvent byrotary evaporation, the residue was dissolved in 500 ml of ethylacetate. The organic phase was washed with deionized water (2×200 ml),1N HCl (3×200 ml), deionized water (200 ml), and brine (200 ml). Thewashed organic layer was then dried over anhydrous sodium sulfate for 15minutes. The solution was filtered and concentrated to one fourth of itsvolume. While stirring, hexane was added slowly to this solution untilpermanent cloudiness appeared. The solution was kept in the freezer tocrystallize the product. After filtration, the residue was dried undervacuum at room temperature yielding 17 grams of the product as anoff-white solid.

Step 3. Synthesis of (neopentyl glycolato)4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronate ester

An oven-dried, 500 ml, 3-necked, round-bottomed, flask was charged with5 grams of 4-(14′-hydroxy-3-thia-1-keto)tetradecyl phenylboronic acidand 100 ml of anhydrous dichloromethane. While stirring, 1 gram ofneopentylglycol was added and the reaction mixture was heated to refluxwith stirring. The heating continued for 3 hours with azeotropicdistillation of water. The reaction mixture was allowed to cool to roomtemperature and the solvent was removed using a rotary evaporator.Anhydrous toluene (50 ml) was added to the residue and the toluene wasremoved using a rotary evaporator. This toluene treatment process wasrepeated once more. The residue was dissolved in 5 ml of dichloromethaneand hexane was added to this solution (with stirring) until cloudinessappeared. The solution was kept in the freezer for recrystallizaton. Theproduct was isolated by filtration, and upon drying, 4.8 grams of thecompound was obtained as an off-white solid.

Step 4. Synthesis of (neopentyl glycolato)4-(14′-bromo-3′-thia-1′-ketotetradecyl)phenylboronate ester

An oven-dried, 500 ml, 3-necked, round-bottomed flask was charged with5.13 grams of the (neopentyl glycolato)4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronate ester and 50 mlof anhydrous dichloromethane. To this solution was added 7.52 grams ofcarbontetrabromide, and the resulting reaction mixture was allowed tostir at 0° C. using an ice bath. A solution of 5.95 grams oftriphenylphosphine dissolved in 10 ml of anhydrous dichloromethane wasadded slowly to the reaction mixture using an addition funnel. Thereaction mixture was stirred at 0° C. and then allowed to warm to roomtemperature slowly. After 16 hours, 20 ml of methanol was added to thereaction mixture. After stirring for 1 hour, the solvent was removed byrotary evaporator. The residue was treated with 200 ml of diethyl etherand stirred for 30 minutes. The mixture was filtered and the solvent wasremoved under reduced pressure. The residue was again treated with etherand the solvent was removed. The resulting residue was flashchromatographed using hexane/ethyl acetate (98/2). After removal of thesolvent, the product was isolated as an off-white solid (yield=4.5grams).

Step 5.4-(14′-trimethylammonium-3′-thia-1′-keto-tetradecyl)phenylboronic acidchloride

A 100 ml, round-bottomed, flask was charged with 500 mg of (neopentylglycolato) 4-(14′-bromo-3′-thia-1′-ketotetradecyl)phenylboronate esterand 5 ml of ethanol. To this solution was added 5 ml of 40% aqueoussolution of trimethylamine. The reaction mixture was stirred at 70° C.for 24 hours. After cooling to room temperature, the solvent was removedunder reduced pressure. The residue was dissolved in 5 ml of methanoland 20 ml 2N HCl. After stirring for 24 hours, the solution wasextracted with ethyl acetate (2×100 ml) to remove the neopentyl glycol.The aqueous solution was extracted with chloroform (3×50 ml). Thechloroform extracts were combined and dried over MgSO₄. Afterfiltration, the solvent was removed under reduced pressure and theresidue was dried under vacuum to give 300 mg of a gummy solid.

Example 5 Synthesis of (neopentyl glycolato)4-(14′-dimethylamino-3′-thia-1′-ketotetradecyl)phenylboronate ester

An oven-dried, 250 ml, 3-necked, round-bottomed flask was charged with2.5 grams of the (neopentyl glycolato)4-(14′-bromo-3′-thia-1′-keto)tetradecyl phenylboronate ester (preparedas described in Example 4, step 4) and 25 ml of anhydroustetrahydrofuran (THF). To this mixture was added 8 ml of 2 Mdimethylamine in THF. After stirring at room temperature for 48 hours,the solvent was removed under reduced pressure. The residue was stirredwith 100 ml of 5% aqueous sodium bicarbonate solution for 1 hour and wasthen extracted with ethyl acetate (2×200 ml). After drying overanhydrous sodium sulfate, the solvent was removed under reduced pressureto yield 1.7 grams of the compound as a gummy solid.

Example 6 Synthesis of4-{14′(3″-chlorotrimethylammium)dimethyl-propylammonium-3′-thia-1′-ketotetradecyl}phenylboronicacid chloride

A 100 ml, round-bottomed, flask was charged with 700 mg of (neopentylglycolato) 4-(14′-dimethylamino-3′-thia-1′-ketotetradecyl)phenylboronateester (prepared as described in Example 5), 400 mg of3-bromopropyltrimethylammonium bromide and 10 ml of ethanol. Thereaction mixture was stirred at 70° C. for 24 hours. After cooling toroom temperature, the solvent was removed under reduced pressure. Theresidue was dissolved in 5 ml of methanol and 40 ml 2 N HCl. Afterstirring for 24 hours, the solution was extracted with ethyl acetate(2×100 ml) to remove neopentyl glycol. The acidified aqueous solutionwas kept in the refrigerator. The precipitated solid was then isolatedby removal of the solvent and dried under vacuum to yield 400 mg of alow melting solid.

Example 7 Synthesis of4-(14′-sulfato-3′-thia-1′-ketotetradecyl)phenylboronic acid sodium salt

A 100 ml, round-bottomed flask was charged with 3 grams of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid (prepared asdescribed in Example 4, step 2) and 25 ml of N,N-dimethylformamide(DMF). To this solution was added 1.6 grams of sulfurtrioxide:DMFcomplex and the resulting reaction mixture was stirred at roomtemperature for 24 hours. To the reaction mixture was added a solution 2grams of NaOH dissolved in 100 ml of water:methanol mixture (1:1) andstirred for 1 hour. The solvent was removed under pressure and theresidue was treated with 100 ml of methanol. After stirring for 1 hour,the reaction mixture was filtered. The filtrate was rotary evaporated todryness, yielding 1.5 grams of an off-white solid.

Example 8 Preparation of 4-(11′-hydroxyundecyl)carboxyphenylboronic acid

A mixture of 4-carboxyphenylboronic acid (1.0 grams), potassium hydrogencarbonate (2.01 g), 11-bromo-1-undecanol, and N,N-dimethylformamide (60mL) was heated at 60° C. under a nitrogen atmosphere for 18 hours. Afterthe heating period, the mixture was allowed to cool to room temperature.The mixture was then filtered and the filtrate was concentrated on arotary evaporator. The concentrated filtrate was diluted with ethylacetate (500 mL) and the ethyl acetate was washed successively withsaturated aqueous sodium bicarbonate (3×300 mL), followed by saturatedaqueous sodium chloride (300 mL). After drying over sodium sulfate, theethyl acetate extract was concentrated on a rotary evaporator and driedunder reduced pressure to afford 2.2 grams of the desired product as alight yellow viscous oil that solidified upon standing to a whitepowder.

The following compounds were synthesized using similar procedures:

from 4-carboxyphenylboronic acid and iodooctadecane;

from 4-carboxyphenylboronic acid and docosyl methane sulfonate;

from bromooctadecane and (3-carboxy-5-nitrophenyl)boronic acid;

from 1-bromodecane and (3-carboxyphenyl)boronic acid;

from 4-carboxyphenylboronic acid and(4-chloropropyl)dimethyloctadecylammonium bromide; and

from 4-carboxyphenylboronic acid and pentethyleneglycol monotosylate.

Example 9 Synthesis of [4-(N,N-dioctadecylcarbamoyl)phenyl]boronic acid

Step 1. Synthesis of 2-(4-carboxyphenyl)-1,3-dioxa-2-borinane

A mixture of 4-carboxyphenylboronic acid (5.0 grams) and 1,3-propanediol(2.5 grams) in toluene (300 mL) was refluxed with a Dean-Stark apparatusfor 6 hours. After the heating period the reaction solution wasconcentrated on a rotary evaporator and dried under reduced pressure toafford 6.39 grams of the desired product as a white solid.

Step 2. Synthesis of 2-(4-carbonylchloride)-1,3-dioxa-2-borinane

To a solution of the above propane diol protected 4-carboxyphenylboronicacid (1.0 grams) in chloroform (5 mL) was added thionyl chloride (3.0mL) and dimethylformamide (100 microliters). The solution was heated toreflux for 2 hours. After the heating period, the reaction solution wasallowed to cool to room temperature and was concentrated on a rotaryevaporator under reduced pressure. To the residue was added chloroform(8 mL) and the resulting solution was concentrated on a rotaryevaporator. The addition of chloroform (8 mL) and the concentrating ofthe solution was repeated twice more. The crude material was dried undervacuum to afford 1.09 grams of the desired product as an off-whitesolid.

Step 3. Synthesis of [4-(N,N-dioctadecylcarbamoyl)phenyl]boronic acid

To a solution of 2-(4-carbonylchloride)-1,3-dioxa-2-borinane (0.8 grams)in chloroform (30 mL) under nitrogen was added dioctadecylamine (1.93grams), triethylamine (1.0 mL), and chloroform (10 mL). The reactionmixture was allowed to stir overnight, afterwhich it was diluted withchloroform (200 mL). The chloroform solution was washed in a separatoryfunnel successively with the following aqueous solutions: 10% HCl (3×100mL), saturated sodium bicarbonate (3×100 mL), and saturated sodiumchloride (100 mL). The chloroform extract was dried over sodium sulfate.2.41 grams of crude material was isolated after filtration andconcentration on a rotary evaporator under reduced pressure. The desiredproduct was purified via column chromatography over silica gel using amixture of ethyl acetate and hexane as eluent.

Example 10 Synthesis of4-(13′-carboxy-3′-thia-1′-ketotridecyl)phenylboronic acid

A 100-mL, three-necked flask was charged with 4-(2′-bromoacetyl)phenylboronic acid (0.95 g, 3.91 mmol) and 20 mL THF. The mixture was degassedby bubbling nitrogen through the reaction mixture for about 20 minutes.11-Mercaptoundecanoic acid (0.9 g, 4.1 mmol) was added to the reactionmixture with stirring under nitrogen. Diisopropylethylamine (1.52 g,2.05 mL, 11.8 mmol) was then added via a syringe over 5 minutes. Thereaction mixture was stirred for 72 hours under nitrogen at roomtemperature. The solvent was removed in vacuo, and the residue waspartitioned between ethyl acetate (100 mL) and water (100 mL). Theorganic extract was washed with 1 N hydrochloric acid (3×100 mL), water(100 mL) and brine (100 mL). The organic extract was dried overmagnesium sulfate and then filtered. The filtrate was then concentratedin vacuo. The residue was dissolved in about 25 mL of hot ethyl acetate.When the mixture was cooled to room temperature, it was placed in afreezer. Product crystallized from the solution. The white crystallinematerial was filtered, washed with cold ethyl acetate, and dried invacuo. 0.93 g (2.45 mmol) of the pure product was obtained. Yield:62.5%.

Example 11 Synthesis of Poly(N-diethanolaminopropyl)acrylamide (17)

The synthesis of Polymer (17) is shown out schematically in FIG. 4. Adetailed description of the procedure is provided below.

Step 1: Synthesis of (N-diethanolaminopropyl)acrylamide (16)

A 2-liter, 3-necked, round-bottomed flask with overhead stirring wascharged with 80.08 grams of N-(3-aminopropyl)diethanolamine and 200milliliters of deionized water. To this mixture was added 3.18 grams ofK₂CO3 and the resulting solution was cooled to less than 5° C. with anice bath. 130 milliliters of dichloromethane with vigorous stirring.This was followed by the addition of 45.0 milliliters ofacryloylchloride (about 1.1 equivalents relative to amine) in 50milliliters of dichloromethane.

A 50% aqueous solution of KOH was prepared by dissolving 20.58 grams ofKOH (about 0.74 equivalents with respect to amine) in 25 milliliters ofdeionized water. About half of the acryloylchloride solution over 30 to45 minutes until the pH between 7 and 8. The KOH solution andacryloylchloride solution were then added dropwise simultaneously,keeping the pH between 8 and 9. The reaction was stirred overnight andallowed to warm to room temperature. The next day, the aqueous layer wasseparated from the organic layer, which was discarded.

The water was removed at 30° C. to 35° C. using a rotary evaporatoruntil orange/brown oil remained. The KCl was filtered during thisprocedure. The oil was then dissolved in 500 milliliters of methanol andstirred for 20 minutes. The remaining KCl was then filtered. Themethanol then removed in vacuo, leaving orange/brown oil. This monomer(16) (126.7 grams) is used directly for polymerization without furtherpurification.

Step 2: Synthesis of Poly(N-diethanolaminopropyl)acrylamide (17)

126.7 grams of Compound (16) was dissolved in 750 milliliters ofdeionized water (about 15% w/v) in a 1-liter, round-bottomed flask. Tothis solution was added 0.4942 grams (about 0.5 wt %) of V-50 initiatoras a solid. The vessel was purged with nitrogen for 30 minutes to obtaina clear, golden-colored and homogeneous solution. The mixture was heatedat 65° C. After about 18 hours of heating, a second batch of V50 (0.2761grams dissolved in 3.0 milliliters of deionized water) was added to thereaction. After about 42 hours of heating, a third batch of V50 (0.2644grams dissolved in 3.0 milliliters of deionized water) was added. Afteranother 72 hours, the heat was removed and the reaction mixture wasallowed to cool to room temperature.

The material was dialyzed (molecular weight cut off 3.5 K) over 24 hourswith a water change after 16 hours. The purified polymer was then driedin a forced air oven at 50° C. for 30 hours. An orange and tacky filmwas obtained and was then redissolved in 300 milliliters of methanol.The solvent was removed in vacuo to yield an oil, which was thenprecipitated into 3 liters of ether. The gummy mass was then vacuumdried at about 35° C. to 40° C. for 16 hours. The final yield of (17)was 50 grams of a grindable, yellow solid (50% recovery).

Example 12 Synthesis of Boronate Ester Functionalized Polymers A.Synthesis of poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid bromide (Polymer:Boronic acid 1:1) (Polymer 1)

178 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 milliliterround-bottomed flask. The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 390 milligramsof4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid bromide. The homogeneous solution was stirred at 40° C. for 1 hour.The solvent was removed under reduced pressure. The residue wasdissolved in 5 milliliters of anhydrous dimethylsulfoxide and theresulting solution was precipitated with anhydrous chloroform. Thisdissolution and precipitation procedure was repeated and the residuedried under vacuum at 35° C. to yield an off white solid. Yield was 488milligrams.

B. Synthesis of poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid bromide(Polymer:Boronic acid, 1:0.5). (Polymer 2)

277 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 milliliterround-bottomed flask. The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 253 milligramsof4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronicacid bromide. The homogeneous solution was stirred at 40° C. for 1 hour.The solvent was removed under reduced pressure. The residue wasdissolved in 5 milliliters of anhydrous dimethylsulfoxide and theresulting solution was precipitated with anhydrous chloroform. Thisdissolution and precipitation procedure was repeated and the residuedried under vacuum at 35° C. to yield an off white solid. Yield was 519milligrams.

C. Synthesis of poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)phenylboronic acidbromide(Polymer:Boronic acid, 1:1). (Polymer 3)

209 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 milliliterround-bottomed flask. The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 450 milligramsof 4-(14′-trimethylammonium-3′-thia-1′-ketotetradecyl)phenylboronic acidbromide. The homogeneous solution was stirred at 40° C. for 1 hour. Thesolvent was removed under reduced pressure. The residue was dissolved in5 milliliters of anhydrous dimethylsulfoxide and the resulting solutionwas precipitated with anhydrous chloroform. This dissolution andprecipitation procedure was repeated and the residue dried under vacuumat 35° C. to yield an off white solid. Yield was 600 milligrams.

D. Synthesis of Poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(13′-trimethylammonium-3′-thia-1′-ketotridecyl)-3-fluorophenylboronicacid bromide (Polymer:Boronic acid, 1:0.5). (Polymer 4)

187 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 milliliterround-bottomed flask The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 253 milligramsof4-(13′-trimethylammonium-3′-thia-1′-ketotridecyl)-3-fluorophenylboronicacid bromide. The homogeneous solution was stirred at 40° C. for 1 hour.The solvent was removed under reduced pressure. The residue wasdissolved in 5 milliliters of anhydrous dimethylsulfoxide and theresulting solution was precipitated with anhydrous chloroform. Thisdissolution and precipitation procedure was repeated and the residuedried under vacuum at 35° C. to yield an off white solid. Yield was 177milligrams.

E. Synthesis of Poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid(Polymer:Boronic acid 1:1) (Polymer 5)

64 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 millilitersround-bottomed flask. The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 113 milligramsof 4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)-3-fluorophenylboronic acid.The homogeneous solution was stirred at 40° C. for 1 hour. The solventwas removed under reduced pressure. The residue was dissolved in 5milliliters of anhydrous dimethylsulfoxide and the resulting solutionwas precipitated with anhydrous chloroform. This dissolution andprecipitation procedure was repeated and the residue dried under vacuumat 35° C. to yield an off white solid. Yield was 90 milligrams.

F. Synthesis of Poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(Polymer:Boronic acid 1:1) (Polymer 6)

243 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 millilitersround-bottomed flask. The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 408 milligramsof 4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid. Thehomogeneous solution was stirred at 40° C. for 1 hour. The solvent wasremoved under reduced pressure. The residue was dissolved in 5milliliters of anhydrous dimethylsulfoxide and the resulting solutionwas precipitated with anhydrous chloroform. This dissolution andprecipitation procedure was repeated and the residue dried under vacuumat 35° C. to yield an off white solid. Yield was 400 milligrams.

G. Synthesis of Poly(N-diethanolaminopropyl)acrylamide Conjugated with4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid(Polymer:Boronic acid 1:0.5) (Polymer 7)

478 milligrams of poly(N-diethanolaminopropyl)acrylamide and 5milliliters of anhydrous methanol were combined in a 50 milliliterround-bottomed flask. The reaction mixture was allowed to stir until aclear solution was obtained. To this solution was added 402 milligramsof 4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid. Thehomogeneous solution was stirred at 40° C. for 1 hour. The solvent wasremoved under reduced pressure. The residue was dissolved in 5milliliters of anhydrous dimethylsulfoxide and the resulting solutionwas precipitated from anhydrous chloroform. This dissolution andprecipitation procedure was repeated and the residue dried under vacuumat 35° C. to yield an off white solid. Yield was 600 milligrams.

H. Synthesis of Poly{N-(2-hydroxy)ethyl ethylenimine) Conjugated with4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid (Polymer 8)

To a solution of 196 mg of poly{N-(2-hydroxy)ethyl ethylenimine}dissolved in 10 milliliters of methanol was added a solution of 1 g of4-(14′-hydroxy-3′-thia-1′-ketotetradecyl) phenylboronic acid dissolvedin 20 milliliter of methanol. The solution was stirred at 40° C. for 30minutes. After removing methanol under reduced pressure, the residue wasextracted with 100 milliliter of warm tetrahydrofuran for 45 minutes.This process was repeated twice. After filtration the residue was driedunder reduced pressure at 35° C. yielding 200 mg of the product as apale yellow solid.

I. Synthesis of Poly{N,N-di(1,2-dihydroxy)propyl diallylamine}Conjugated with 4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronicacid (Polymer 9)

To a solution of 366 mg of poly{N,N-di(1,2-dihydroxy)propyldiallylamine} dissolved in 25 milliliters of methanol was added asolution of 1 g of 4-(14′-hydroxy-3′-thia-1′-ketotetradecyl)phenylboronic acid dissolved in 20 milliliter of methanol. The solutionwas stirred at 40° C. for 30 minutes. After removing methanol underreduced pressure, the residue was extracted with 100 milliliter of warmtetrahydrofuran for 45 minutes followed by 100 milliliter of warm ethylacetate for 30 minutes. After filtration the residue was dried underreduced pressure at 35° C. yielding 250 mg of the product as a paleyellow solid.

Example 13 Polymers of the Present Invention Inhibit Lipase Activity InVitro

An in vitro assay of pancreatic lipase activity was used to measure theefficacy of lipase inhibitory compounds. Porcine pancreatic lipase (23units/milliliters) was incubated for 4 hours at 37° C. with 72 mMtriglyceride (as an olive oil/gum arabic emulsion) in 5.5 milliliters ofa 300 mM BES buffer, pH 7.0, containing 10 mM CaCl₂, 109 mM NaCl, and 8mM sodium taurocholate. The reaction was stopped by acidification withHCl and the lipids were extracted by the disclosed in Folch, et al., J.Biol. Chem. 226:497 (1957) prior to analysis by HPLC. An aliquot of thechloroform layer was evaporated and reconstituted in hexane, and thesample was analyzed on a Waters Alliance 2690 HPLC with a Sedex 55Evaporative Light Scattering detector utilizing a YMC PVA Sil 3×50millimeter column. The mobile phase consisted of hexane and methylt-butyl ether delivered in a linear gradient at a flow rate of 0.5milliliters/minute. External standards were utilized for quantitation oftriglycerides, diglycerides, and fatty acids, and the percent lipolysiswas determined. For evaluation of lipase inhibitor efficacy, compoundswere dissolved in DMSO or another appropriate solvent and added directlyto the assay mixture prior to incubation. Inhibition was determinedrelative to a control incubation and IC₅₀ values were calculated from aplot of % inhibition vs. inhibitor concentration. IC₅₀ values are shownin the Table. As can be seen, the polymes tested are effectiveinhibitors of lipase.

Example 14 Polymers of the Present Invention Inhibit Lipolysis In Vivo

Compounds were evaluated in rats to determine their in vivo potency ininhibiting fat absorption through lipase inhibition. Rats wereacclimated to the facility for approximately 1 week in individualwire-bottom cages and provided a standard chow diet and water adlibitum. Rats were then randomly assigned to groups of 4. They weregavaged at (7-8 AM) with 4 milliliters olive oil emulsified with gumarabic, with or without drug following an 18 hour fast. Test compoundswere dissolved in DMSO or deionized water. Drug solutions were mixedthoroughly in the olive oil emulsion just prior to administration. After8 hours, rats were euthanized with CO₂ and the intestines were removed.The intestinal contents were harvested from the lower half of the smallintestine and the cecum. Contents were placed in separate, pre-weighed,15 milliliter conical screw cap tubes in a (dry ice/alcohol bath) tomaintain freezing temperature until the final freeze of all samples.Samples were stored at −80° C. until lyophilization.

Samples were freeze-dried and ground, then analyzed for triglyceride andfatty acid.

A 20 milligram aliquot of each sample was weighed and transferred to a15 milliliters conical tube. 3 milliliters of hexane were added to eachtube, which were capped and vortexed for 15 seconds at high speed. 3milliliters of 1 N HCl were added and the samples were then subjected towrist-action shaking for 1 hour. Samples were then centrifuged for 5minutes at 3500 rpm and the hexane layer was collected. An aliquot ofthe hexane layer was diluted in hexane and analyzed for triglyceride,diglyceride and fatty acid by HPLC as described above.

The data was expressed as follows. The milligrams of intestinal contentsthat was extracted and the total number of milligrams collected wererecorded. The milligrams/milliliters values obtained from the HPLCanalysis were entered. The individual lipid components were calculatedand expressed as total milligrams recovered. Dose units are expressed asthe milligrams of drug per gram of oil administered to each rat. TheED₅₀'s were determined by extrapolating the dose value at half themaximum obtainable triglyceride recoverable in the assay. The resultsare shown in the Table. As can be seen, the polymers are effective ininhibiting lipolysis in vivo. The Table Inhibition of in vitro and invivo lipolysis In Vivo In Vitro In Vivo Infusion Assay in PancreaticLipase Infusion Assay in Rats Ed₅₀ (mg/kg Polymer Assay IC₅₀ (μg/g RatsED₅₀ (mg/g body wt) or Compound fat) or estimate fat) or estimateestimate Polymer 1 5.2 3 22.5 Polymer 2 5.3 4.5 33.8 Polymer 3 16.0 20150 Polymer 4 not assayed not assayed not assayed Polymer 5 4.5 50 375Polymer 6 15 36 270 Polymer 7 10 not assayed not assayed

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-100. (canceled)
 101. A method of treating a subject afflicted with acondition selected from Type II diabetes mellitus, impaired glucosetolerance, hypertension, coronary thrombosis, stroke, lipid syndromes,hyperglycemia, hypertriglyceridemia, hyperlipidemia, sleep apnea, hiatalhernia, reflux esophagisitis, osteoarthritis, gout, gallstones, kidneystones, pulmonary hypertension, infertility and cardiovascular disease,the method comprising the step of administering to the subject aneffective amount of a polymer comprising one or more groups selectedfrom pendent aryl boronate ester groups, pendent aryl boronamide groupsand aryl boronate thioester groups, wherein the groups are representedby a structural formula selected from:

or a pharmaceutically acceptable salt of said polymer, wherein Ar is asubstituted or unsubstituted aryl group; and each Z is —O—, —NH— or —S—and is independently selected.
 102. The method of claim 101 wherein eachZ is —O—.
 103. The method of claim 102, wherein the polymer comprisesone or more pendent aryl boronate ester groups represented by astructural formula selected from:

wherein the Phenyl Ring is substituted or unsubstituted, or apharmaceutically acceptable salt of said polymer.
 104. The method ofclaim 103 wherein the Phenyl Ring is substituted with one or moreelectron withdrawing groups.
 105. The method of claim 104 wherein thependent phenyl boronate ester groups are represented by a structuralformula selected from:

wherein: X is an electron withdrawing group; R is a substituted orunsubstituted straight chained hydrocarbyl group optionally containingone or more ether, thioether, phenylene, amine or ammonium linkage; andthe Phenyl Ring is substituted or unsubstituted.
 106. The method ofclaim 105 wherein X is —CHD-, —CD₂—, —CO—, —CONH—, —COO—, —S(O)—,—S(O₂)O— or —SO₂—; the Phenyl Ring is optionally substituted with one ormore electron withdrawing groups; D is a halogen; and R is a straightchained hydrocarbyl group with an ether or thioether linkage and issubstituted at the terminal position with an amine, halogen, —CF3,thiol, ammonium, alcohol, —COOH, —SO₃H, —OSO₃H or phosphonium group.107. The method of claim 106 wherein X is —CHD-, —CD₂—, —CO—, —CONH—,—COO— or —SO₂—.
 108. The method of claim 105 wherein X is —CHD-, —CD₂—,—COO—, —CONH—, —CO— or —SO₂—; the Phenyl Ring is optionally substitutedwith one or more electron withdrawing groups; D is a halogen; and R is astraight chained hydrocarbyl group with an ether or thioether linkageand is substituted at the terminal position with—[NH—(CH₂)_(q)]_(r)—NH₂), wherein q is an integer from 2 to about 10 andr is an integer from 1 to about 5, provided that one or more of thesecondary amines in —[NH—(CH₂)_(q)]_(r)—NH₂) are optionally N-alkylatedor N,N-dialkylated and the primary amine in —[NH—(CH₂)_(q)]_(r)—NH₂) isoptionally N-alkylated, N,N-dialkylated or N,N,N-trialkylated.
 109. Themethod of claim 103, wherein the polymer comprises one or more pendentphenyl boronate ester groups represented by a structural formulaselected from:

R is a substituted or unsubstituted straight chained hydrocarbyl groupoptionally containing one or more ether, thioether, phenylene, amine orammonium linkage; and the Phenyl Ring is substituted or unsubstituted;or a pharmaceutically acceptable salt of said polymer.
 110. The methodof claim 109 wherein the Phenyl Ring is optionally substituted with oneor more additional electron withdrawing groups; R is a straight chainedhydrocarbyl group optionally comprising an ether or thioether linkage;and R is substituted at the terminal position with an amine, halogen,—CF3, thiol, ammonium group, alcohol, —COOH, —SO₃H, —OSO₃H orphosphonium group.
 111. The method of claim 110 wherein R is a straightchained hydrocarbyl group comprising an ether or thioether linkage andsubstituted at the terminal position with an ammonium group.
 112. Themethod of claim 110 wherein R is a straight chained hydrocarbyl groupcomprising an ether or thioether linkage and substituted at the terminalposition with a trialkyl ammonium group.
 113. The method of claim 110wherein R is a straight chained hydrocarbyl group comprising an ether orthioether linkage and substituted at the terminal position with atrimethyl ammonium group.
 114. The method of claim 109 wherein thePhenyl Ring is optionally substituted with one or more additionalelectron withdrawing groups; R is a straight chained hydrocarbyl groupwith an ammonium linkage and optionally substituted at the terminalposition with an amine, halogen, —CF3, thiol, ammonium group, alcohol,—COOH, —SO₃H, —OSO₃H or phosphonium group.
 115. The method of claim 109wherein the Phenyl Ring is optionally substituted with one or moreadditional electron withdrawing groups; R is a straight chainedhydrocarbyl group with an ammonium linkage.
 116. The method of claim 109wherein the Phenyl Ring is optionally substituted with one or moreadditional electron withdrawing groups; R is a straight chainedhydrocarbyl group substituted at the terminal position with an amine,halogen, —CF3, thiol, ammonium group, alcohol, —COOH, —SO₃H, —OSO₃H orphosphonium group.
 117. The method of claim 116 wherein R is a straightchained hydrocarbyl group substituted at the terminal position with anammonium group.
 118. The method of claim 116 wherein R is a straightchained hydrocarbyl group substituted at the terminal position with atrialkyl ammonium group.
 119. The method of claim 105 wherein —XR is—C(O)CH₂—O[—(CH₂)pO]m-(CH₂)p-Y or —C(O)CH₂—S[—(CH₂)pO]m-(CH₂)p-Y, p is 2or 3, m is an integer from 1-5 and Y is an ammonium group.
 120. A methodof inhibiting the uptake of fat in the gastrointestinal tract of asubject in need of such treatment, wherein the subject is afflicted witha condition selected from Type II diabetes mellitus, impaired glucosetolerance, hypertension, coronary thrombosis, stroke, lipid syndromes,hyperglycemia, hypertriglyceridemia, hyperlipidemia, sleep apnea, hiatalhernia, reflux esophagisitis, osteoarthritis, gout, gallstones, kidneystones, pulmonary hypertension, infertility and cardiovascular disease,said method comprising the step of administering to the subject aneffective amount of a polymer comprising one or more groups selectedfrom pendent aryl boronate ester groups, pendent aryl boronamide groupsand aryl boronate thioester groups, wherein the groups are representedby a structural formula selected from:

or a pharmaceutically acceptable salt of said polymer, wherein Ar is asubstituted or unsubstituted aryl group; and each Z is —O—, —NH— or —S—and is independently selected.